Schizophrenia is a neurodevelopmental disorder that affects young adults and is manifested by a disruption in cognition and emotion, along with negative (i.e., apathy, poor or nonexistent social functioning) and positive (presence of hallucinations, delusions) symptoms, and a lifetime prevalence of 1%. Our proposal will evaluate the degree of involvement of GABAergic receptor families, Reelin, and GAD65 and GAD67 kDa and their constituent signaling systems in postmortem brain samples of subjects with schizophrenia vs. subjects with bipolar disorder, major depression, and matched controls. The central hypothesis of this application is that expression of molecules involved in the Reelin and GABAergic signaling pathways are altered in subjects with schizophrenia, bipolar disorder, and major depression resulting in dysfunctional signaling and consequent brain abnormalities in these disorders. We plan to test our central hypothesis and accomplish the objectives of this application by pursuing the following three Specific Aims: 1) Systematically determine mRNA and protein levels for members of the Reelin signaling system in frontal cortex, anterior hippocampus, and lateral cerebellum of subjects with schizophrenia vs. subjects with bipolar disorder, major depression, and matched controls; 2) Determine the mRNA and protein levels of GAD65, GAD67, and selected GABA receptors in frontal cortex, anterior hippocampus, and lateral cerebellum of subjects with schizophrenia vs. subjects with bipolar disorder, major depression, and matched controls; and 3) Characterize microRNA and miRNA target gene expression in frontal cortex, hippocampus, and cerebellum of subjects with schizophrenia vs. subjects with bipolar disorder, major depression, and controls. We will employ previously established qRT-PCR, western blotting, immunocytochemistry, in situ hybridization and miRNA microarray techniques to quantify various mRNA and protein species. This proposal has the potential to accomplish multiple objectives: 1) Discover systematic changes in Reelin, its receptors, and downstream molecules, in key abnormal structures in schizophrenia, bipolar disorder and major depression: frontal cortex (Brodman's area (BA) 6), anterior hippocampus, and lateral cerebellum; 2) Determine coordinated changes in molecules and identifying relationships among molecules of the Reelin signaling system; 3) Characterize changes in the mRNA and protein levels for GABA receptors, GAD65 and GAD67 kDa molecules in anterior hippocampal, lateral cerebellar, and frontal cortices of subjects with schizophrenia vs. matched bipolar, depressed, and healthy controls; 4) Discover relationships among Reelin and GABAergic signaling system molecules that explain dysfunction of these two systems in the pathology of schizophrenia, bipolar disorder, and major depression; and 5) Test whether miRNAs may be responsible for altered expression of Reelin and GABAergic signaling molecules in subjects with schizophrenia, bipolar disorder, and major depression.